Ibuprofen per se is a poorly water soluble drug with a melting point in the 75.degree.-77.degree. C. range. Ibuprofen is prescribed and sold, and now sold over-the-counter, as a pain relieving, fever-reducing and antiinflammatory drug. In some patient populations ibuprofen must be taken regularly in dosages up to or greater than about 3200 mg./day to alleviate the pain or other symptoms associated with the inflammatory disease being treated. The implications of these daily dosages is that a patient must take large amounts of ibuprofen in the form of tablets or capsules to maintain the desired effective dose of ibuprofen each day.
Currently, ibuprofen is formulated for sale by manufacturers in coated compressed tablets containing from 200 mg. to 600 mg. of ibuprofen per tablet. Those in the art would like to have higher dose ibuprofen tablets or capsules so that the patient needing same would only have to take a minimal number of tablets or capsules to maintain the desired dosage of ibuprofen per day regimen. This would also aid in patient compliance with the medication.
Manufacturers of ibuprofen formulations would also desire to prepare one ibuprofen granulation formulation which is adaptable to further processing with or without the addition of acceptable pharmaceutical excipients such as lubricants, diluents and binders for formulation of the high ibuprofen content, final, finished tablet or filled capsule dosage form, in a variety of dosage strengths as desired by marketers, physicians, pharmacists and patients.
However, the chemical and physical properties of ibuprofen, per se, the physical form it is obtained from ibuprofen per se suppliers thereof, the need for large volumes of ibuprofen per se and pharmaceutical formulations thereof to satisfy the need and market therefor, the current wet granulation and direct compression formulation methods are unsuitable for making large percentage (over 73% by weight) high dose ibuprofen pharmaceutical tablet formulations for patients and drug manufacturers alike for a number of reasons. Low bulk density of ibuprofen per se, as it is currently obtained from chemical suppliers thereof causes the need for rather large tablet and capsule forms of the final high dose pharmaceutical formulations of such low density ibuprofen. The size of the punches of the tablet making machines must be correspondingly large to obtain the necessary fill weight. Attempts to minimize the inclusion of desirable pharmaceutical excipients to keep the size of the punch and tablet (or capsule) size down results in tablets with undesirable properties. Extrapolating these manufacturing difficulties to the making of pharmaceutically "elegant" high dose ibuprofen tablets (i.e., greater then 800 mg.) by currently known wet granulation techniques only emphasizes that there will be obtained a large ibuprofen tablet that will be difficult for some patients to swallow and thus be unacceptable to them, and thus to the progression of decision makers in the course of manufacturing such an ibuprofen tablet or capsule product.
Moreover, currently produced ibuprofen wet granulation formulations tend to "age" over time, as the tablets or capsules sit in warehouses and drugstore shelves, thereby lowering the rate of dissolution of the ibuprofen. This `aging` property is illustrated by accelerating this `aging` under conditions of high temperature (40.degree.-60.degree. C.) and/or humidity in laboratory studies. This aging phenomenon appears as a decrease in the in vitro dissolution rate of the ibuprofen-containing product by standard test methods. This reduction in dissolution rate has been theorized as being attributed to the scintering of the bulk ibuprofen. Scintering is a type of "cementing" of the ibuprofen drug particles to one another. The thermal mobility of the surface ibuprofen molecules is believed to increase as temperature of the ibuprofen particles is increased to approximately one-half to two-thirds of the melting point of ibuprofen (Ibuprofen MP--75.degree.-77.degree. C.). This increased mobility of the ibuprofen particles is believed to result in diffusion of the ibuprofen molecules between contact points in the formulation being tested. (See W. Pietsch, "Fundamentals of Agglomeration", an industrial workshop presented at the Powder and Bulk Solids Conference/Exhibition, Chicago, Ill., USA, in May, 1984.) As a result of this scintering, solid ibuprofen bridges are formed between ibuprofen particles which effectively reduce the ibuprofen drug surface area available for dissolution over time. Other drug substances have exhibited the same lowering of dissolution rate over time phenomenon and some have required special manufacturing and/or formulation procedures to minimize the drug particle-to-drug particle contact or scintering thereof.
A typical way in the pharmaceutical formulation art to minimize scintering of drug molecules in a solid drug formulation has been to increase the level or percentage of excipients or diluents in order to further isolate the individual drug particles from one another. This excipient increase or further dilution action becomes prohibitive where it is desired to make high drug percentage content ibuprofen drug formulations, i.e., high dose tablets or filled capsules, because such tablets or capsules made from currently used wet granulation ibuprofen formulations result in final tablets or capsules which are too large to be acceptable to the majority of the patient population which might otherwise desire this large dose of ibuprofen.
Attempts to make active drug granulations into a higher bulk density physical form in order to reduce the volume or size of tablet or capsule needed for a desired dosage per unit has been tried, but with ibuprofen, some methods normally used to increase bulk density per unit volume of drug actually promote scintering or "cementing" of the drug thereby adversely affecting the drug dissolution rate.
In doing the research which led to this invention approximately fifty pharmaceutical formulations containing ibuprofen as the high percentage content active drug component therein were tried before this invention was recognized or definable, and an acceptable ibuprofen dry granulation prototype formulation described and claimed herein was developed. The major problems with the majority of those approximately fifty ibuprofen formulations were:
1. Inadequate bulk density of the ibuprofen granulations to obtain a reasonably sized tablet.
2. Punch filming, picking or sticking during compression of the resulting ibuprofen granulations.
3. Poor flowing granulation formulations, which are difficult to handle in typical pharmaceutical plant scale equipment.
4. Excessive disintegration times of tablets made from the ibuprofen granulations.
5. Lamination and friability problems with tablets made from the ibuprofen granulations.
6. The use of alcohol, e.g., ethanol, as part of a wet granulation ibuprofen premix preparation, requires special equipment in a pharmaceutical plant, which would be desirably avoided.
7. Because of the high dosage strengths involved, only minimal amounts of pharmaceutical excipients could be added to overcome the above problems (i.e., punch filming, poor flow, excessive disintegration times, lamination, etc.) In addition, besides the above problems facing an industrial pharmacist or pharmaceutical engineer, there is the concern that in some cases, the source of supply of certain types of the bulk ibuprofen drug per se may not be reliable or dependable. Thus, the industrial pharmacist or pharmaceutical engineer must discover process conditions, choices and proportions of ingredients to process available sources of ibuprofen to make processable high ibuprofen drug content dry granulation formulations and final formulations (i.e., tablets and capsules) which will overcome the above problems, acceptable to the pharmaceutical industry, physicians and the pharmacists and patient populations alike.
A Torode et al U.S. Pat. No. 4,209,513 discloses a wet water and alcohol granulation method for making a compressed tablet containing a high content (80% to 98%, W/W) of a combination of a 2,4-diaminopyrimidine and a sulfonamide antimicrobial drug formulation containing not more than 20% W/W of a granulating and disintegrating agent, the combination having a particle size less than 40 micrometers, and the disintegrating agent having a swelling capacity greater than 5 ml./gram. However, the brand named disintegrating agents referred to therein, including those for the low viscosity sodium carboxymethylcellulose such as Capagel, and the starch, cellulose derivatives, gelatin and polyvinylpyrrolidine granulating agents, referred to therein are not effective in obtaining the ibuprofen dry granulation formulations described herein. Moreover, the use of alcohol now requires special explosion and fireproof equipment that is expensive and best avoided if possible.
Those in the art continue to do research to find improved cost efficient methods for preparing uniform high percentage ibuprofen granulation formulations which are adaptable for further use in compounding a number of desirable high strength ibuprofen drug end product forms and sizes which will still have all of the above stated chemical and physical properties and be acceptable to patients.